Obesity and its associated disorders, represent major health problems in all industrialized countries. Obesity, defined as an excess of body fat relative to lean body mass, has been directly linked to increased incidences of diseases such as coronary artery disease, stroke, and diabetes, and is one of the factors, whose presence defines “Syndrome X”.
At the center of “Syndrome X” and “Metabolic Syndrome”, is the common feature of tissue resistance to the action of insulin. This impaired biological response to insulin is manifested in the metabolic and vascular effects of insulin. The most common presentation of Syndrome X is associated with obesity.
The adaptive response to insulin resistance (IR) in individuals produces compensatory hyperinsulinaemia. As subjects progressively insulin resistant, they manifest varying degrees of change in clinical parameters, including blood pressure, and/or increased levels of serum glucose, and/or cholesterol and/or triglycerides, and/or uric acid, and/or factors that increase coagulation. Once these clinical parameters have changed enough, the patient may differentially manifest well-recognized clinical conditions, including: type 2 diabetes, hypertension (high blood pressure), hyperlipidemia or dyslipidemia, particularly (but not limited to) hypertriglyceridemia, hyperuricemia or gout, and hypercoagulability (defined as an abnormal, increased tendency for clots to form, particularly inside blood vessels). These clinical conditions are well-recognized risk factors for cardiovascular (coronary artery and cerebrovascular) disease.
The treatment of factors contributing to IR (e.g., obesity) or the treatment of IR itself improves many of the clinical conditions which at first glance appear to be unrelated. For example, dieting alone or pharmacotherapeutic agents that induce weight loss will decrease blood pressure, blood glucose and triglycerides. Agents that are designed to improve insulin sensitivity can also favorably alter blood pressure, lipids, and blood glucose.
Diabetes mellitus is characterized by metabolic defects in production and utilization of carbohydrates, resulting in elevated blood glucose or hyperglycemia due to the failure to maintain appropriate blood sugar levels. Research in the treatment of diabetes has centered on attempts to normalize fasting and postprandial blood glucose levels. Current treatments include administration of exogenous insulin, oral administration of drugs and dietary therapies and exercise regimens.
Two major forms of diabetes mellitus are recognized. Type 1 diabetes, or insulin-dependent diabetes, is the result of an absolute deficiency of insulin, the hormone which regulates carbohydrate utilization. Type 2 diabetes, or non-insulin dependent diabetes, often occurs with normal, or even elevated levels of insulin and appears to be the result of the inability of tissues to respond appropriately to insulin. Complications of type 2 diabetes include retinopathy, nephropathy, neuropathy, and coronary heart disease, and are believed to be triggered by excessive protein glycation, which in turn results from excessive levels of circulating glucose.
New innovative approaches are urgently needed at both the basic science and clinical levels to develop compounds which are useful for treating, suppressing, inhibiting or reducing the incidence of a) Diabetes; b) glucose intolerance; c) hyperinsulinemia; d) insulin resistance; e) dyslipidemia; f) cachexia; g) hypercholesterolemia; h) high blood pressure; i) cardiovascular disease or disorder; j) atherosclerosis; k) stroke; l) cerebrovascular conditions; and diseases, disorders or conditions related thereto.